Article

Immunosuppressive Agents for Uveitis

Addition of immunomodulatory therapy increases disease remission and limits steroid use.

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Noninfectious ocular inflammation, either acute or chronic, is a significant cause of ocular morbidity and visual impairment. Corticosteroids, both locally and systemically, have been a longstanding, effective mainstay of treatment, but their use is limited by ocular and systemic side effects. As such, immunomodulatory agents have been increasingly introduced as steroid-sparing treatments when inflammation cannot be controlled by steroids alone or as adjunctive treatments to primary steroid therapy to achieve adequate control of inflammation.

Immunomodulating drugs have been shown to be highly effective at preserving visual function and limiting ocular and systemic complications. Since these drugs take several weeks to take effect, the immunosuppressive regimen typically includes initial high-dose oral corticosteroids, followed by the introduction of an immunomodulating drug. Once the inflammation is controlled, a slow taper of corticosteroids is initiated. If there is disease activity despite corticosteroid therapy, then dual therapy with high-dose, usually oral, corticosteroids, along with an immunomodulating drug, is administered.1 The choice of drug is based upon proven efficacy for given disease processes, steroid-sparing effects, side-effect profiles, and ease of administration.

The immunomodulating drugs can be further categorized into antimetabolites, T-cell inhibitors, alkylating agents, and biologic agents.

ANTIMETABOLITES

Azathioprine

Azathioprine (Imuran, Prometheus Laboratories) is a purine nucleoside analog, a prodrug metabolized by the liver, and it alters purine metabolism, limiting DNA and RNA synthesis. Azathioprine has been shown to be most effective at controlling chronic uveitis, especially in combination with oral steroids. The effective dosing ranges from 1 to 3 mg per kg per day. Metabolism of azathioprine is halted by the drug allopurinol (Zyloprim, Prometheus Laboratories), so care should be taken when treating patients with a history of gout. Nausea, vomiting, and hepatic disease are the most common side effects; however, reversible bone marrow suppression is the most severe side effect. In patients receiving azathioprine post-renal transplant, an increased risk of malignancy has been observed.1 As such, a complete blood count (CBC) should be performed every 4 to 6 weeks, along with liver function tests every 12 weeks.1

Methotrexate

Methotrexate (MTX), the first-line antimetabolite, is a folic acid analog and dihydrofolate reductase inhibitor, also interfering with DNA synthesis. In a retrospective case series of 160 patients with noninfectious uveitis, MTX was shown to be effective at reducing ocular inflammation in 76.2% of patients, obviating the need for steroids in 56% of patients and preserving visual acuity in 90% of patients. Eighteen percent of patients discontinued the medication due to side effects.2 However, MTX is well tolerated in children and is effective for the treatment of juvenile idiopathic arthritis (JIA)-associated uveitis. MTX can be administered orally, subcutaneously, or intravenously. Typically, dosing ranges from 7.5 to 25 mg once per week in a single dose, with 15 mg once weekly being the most common dosing. Folate is administered with methotrexate to minimize gastrointestinal-related side effects. Hepatotoxicity and cytopenias are also common side effects. As such, at the time of initiating therapy, a CBC, chemistry panel, hepatitis B surface antigen, and hepatitis C antibody are obtained. Routine monitoring of CBC and liver function testing are recommended every 1 to 2 months.1

Mycophenolate Mofetil

Mycophenolate mofetil (CellCept, Genentech) is a selective inhibitor of guanosine nucleotide synthesis, limiting lymphocyte proliferation. In a randomized clinical trial comparing mycophenolate to methotrexate for the treatment of noninfectious uveitis, there was no difference in steroid-sparing role, control of inflammation, or adverse events between the 2 drugs, although there was a 22% difference in treatment success favoring methotrexate.3 It is typically dosed at 1 g twice daily. Diarrhea, nausea, vomiting, leukopenia, lymphoma, skin cancer, and opportunistic infections have been reported. Patients are initially monitored on a weekly basis for 4 weeks and then twice monthly for 2 months, with monthly testing thereafter. Liver function tests are also checked every 3 months.1

T-CELL/CALCINEURIN INHIBITORS

Cyclosporine

Cyclosporine is produced by fungi and binds to T lymphocytes, blocking replication and the production of lymphokines. The use of cyclosporine is limited by its hypertensive and nephrotoxic side effects. Safe dosing ranges from 2 to 5 mg/kg/day orally administered but does not eliminate the risk of side effects. The multicenter Systemic Immunosuppressive Therapy for Eye Diseases Cohort (SITE) study found that cyclosporine achieved sustained monotherapy control in only 33.4% of patients at 6 months. There was a minimum degree of inflammation present in 25% of all patients during the study period.4

Tacrolimus

Tacrolimus is a macrolide antibiotic that inhibits the activation of T lymphocytes. Similar in mechanism of activation to cyclosporine, tacrolimus is also limited by its side effect profile of nephrotoxicity and hypertension. In a study of 37 patients with noninfectious posterior uveitis requiring second-line therapy with either tacrolimus or cyclosporine, there was similar steroid-sparing efficacy between the 2 groups, while cyclosporine had higher rates of adverse effects.5 Tacrolimus can be administered orally or intravenously, with an initial oral dose of 0.05 mg per kg per day and with ongoing monitoring of tacrolimus levels.

ALKYLATING AGENTS

Cyclophosphamide

Cyclophosphamide (Cytoxan, Bristol-Myers Squibb) is a nonspecific alkylating agent that alters the composition of DNA bases, resulting in cell death and the suppression of the immune response. The use of this drug has been limited by its association with significant toxicity, including hemorrhagic cystitis, malignancy, teratogenicity, female and male gonadal dysfunction, and myelosuppression. While retrospective studies have demonstrated its effectiveness in sustained control of inflammation and steroid-sparing effects in the treatment of uveitis, scleritis, and ocular mucous membrane pemphigoid,6 its use has been limited practically to disease processes refractory to first-line treatment, given the side effect profile. Cyclophosphamide has been administered orally and also in intravenous pulse therapy, which has not been found to be effective for uveitis.1 Orally, dosing is started at 2 mg per kg per day with dosing adjustments based on response and toxicity. A CBC and urinalysis are obtained weekly and then, once dosing is stable, every 4 weeks. A normal lowering of the white blood cell count is observed, but treatment is often discontinued at counts less than 2,500 cells per µL. Additionally, patients are encouraged to consume at least 2 L of fluids daily to minimize the risk of cystitis. With respect to gonadal teratogenicity, cryopreservation of eggs or sperm can be performed prior to initiating therapy.1

Chlorambucil

Chlorambucil is an alkylating agent that interferes with DNA replication. Like cyclophosphamide, the use of chlorambucil is limited by its side effect profile. As such, it is favored and shown to be effective in ocular inflammation refractory to first-line treatment.7 Chlorambucil is administered orally as a long-term, low-dose treatment of 0.1 to 0.2 mg per kg per day and also as a short-term, high-dose therapy starting at 2 mg weekly, with increased dosing per week until suppression of inflammation.1 Bone marrow suppression is the most common side effect, and a CBC is performed weekly while titrating dosing and then monthly once dosing is stabilized.

BIOLOGIC AGENTS

Deregulation of inflammatory cytokines has been found to play a key role in autoimmune-mediated diseases. Therefore, there has been increasing use of biologics, or drugs manufactured by recombinant DNA, to target the inflammatory pathways implicated in uveitis. Initially developed to treat systemic inflammatory diseases, biologics have not yet been approved by the FDA for the treatment of ocular inflammation, but off-label use has yielded significant information regarding the efficacy of these medications for noninfectious uveitis.

Infliximab

Infliximab (Remicade, Janssen Biotech) is a partially murine monoclonal antibody against free and bound TNF alpha. It is administered intravenously at doses of 5 to 10 mg/kg. It has been shown to be particularly effective in uveitis related to Beh├žet’s disease and in JIA. In a prospective, observational study comparing infliximab infusion, intravenous methylprednisolone, and intravitreal triamcinolone acetonide, there was significantly faster resolution of inflammation in patients receiving infliximab.8 Significant side effects of this medication include lupus-like syndrome, thromboembolism, and the formation of solid tumors.9 In a retrospective case series of 88 patients with chronic refractory uveitis treated with infliximab, 23% achieved suppression of inflammation while being treated with infliximab alone, while 36% experienced at least one side effect, and 19% discontinued therapy.10

Adalimumab

Adalimumab (Humira, AbbVie) is a humanized monoclonal antibody against TNF alpha. It can be self-administered subcutaneously every 2 weeks. The safety and efficacy of adalimumab have been confirmed with prospective, multicenter data.11 Recently, the efficacy of adalimumab in the treatment of refractory noninfectious uveitis has been studied in 2 multinational phase 3 clinical trials: VISUAL 1 and VISUAL 2. VISUAL 1 enrolled individuals with 217 patients with active noninfectious uveitis, while VISUAL 2 enrolled patients with inactive, steroid-dependent noninfectious uveitis. In both studies, patients were randomized to adalimumab or placebo subcutaneous injections. Treatment failure rates were significantly lower in patients receiving adalimumab compared to placebo. Adverse events were limited but included malignancy, active tuberculosis, lupus, and demyelinating disease. Screening for these diseases prior to initiating treatment is necessary.12,13

Rituximab

Rituximab (Rituxan, Genentech) is a monoclonal antibody against CD20+ B lymphocytes. It has been shown to be effective in patients with noninfectious uveitis refractory to first-line treatment. A retrospective review of 8 patients treated with rituximab for refractory JIA-associated uveitis showed effectiveness in improving intraocular inflammation and steroid-sparing effects. Patients received an initial dose of 1,000 mg infused intravenously, followed by a second infusion two weeks later.14 Side effects of rituximab included severe infusion reaction and reactivation of latent hepatitis B. Hepatitis screening is necessary prior to initiating treatment.

Abatacept

Abatacept (Orencia, Bristol-Myers Squibb) is a soluble fusion protein that functions to block activation of T cells. It is administered by monthly intravenous infusions with a starting dose of 10 mg/kg, and it has been shown to be effective in controlling refractory JIA-associated uveitis in limited case series.15

Additional but less well-studied biologic agents for the treatment of noninfectious uveitis include golimumab (Simponi, Janssen Biotech; anti-TNF alpha monoclonal antibody), gevokizumab (Xoma Corporation; anti-interleukin 1 beta monoclonal antibody), tocilizumab (Actemra, Genentech; anti-interleukin 6 receptor monoclonal antibody), alemtuzumab (Lemtrada, Sanofi Genzyme; anti-CD52 monoclonal antibody), secukinumab (Cosentyx, Novartis; anti-interleukin 17A monoclonal antibody), and interferon.

MALIGNANCY RISK

While the above agents have been shown to be effective in the management of noninfectious uveitis in retrospective and/or prospective studies, there has been ongoing concern regarding the increased risk of malignancy associated with these drugs. Potential mechanisms identified include interruption of immune surveillance for the destruction of malignant cells, increased susceptibility to infection with oncogenic agents, and the pharmacologic effects on DNA or DNA metabolism. Since carcinogenesis requires many years, available studies are limited in their follow-ups to determine a clear relationship between immunomodulating drugs and malignancy risk. Alkylating agents, such as cyclophosphamide and chlorambucil, have been the most strongly implicated in increased risk of malignancy. Use of these agents for limited durations for the treatment of severe, vision-threatening disease is supported by the literature. Nonalkylating agent immunomodulatory drugs likely do not increase cancer risk to a degree that outweighs the benefits of treatment.16

CONCLUSION

Steroids are still the first-line treatment for the treatment of noninfectious uveitis. However, when long-term treatment is expected, and/or inflammation is not completely controlled by steroids, the addition of immunomodulatory drugs significantly increases the rate and duration of disease remission and limits the long-term use of steroids and their associated side effects. The choice of immunomodulatory drug is dependent on the clinical features of the uveitis, the bioavailability and administration of the drug, the patient’s health and risk factors for disease, the side effect profile of the drug, and the response to treatment. RP

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